An efficient synthesis of an enantiomerically pure phosphonate analogue of L-GABOB

Article abstract of DOI:10.1016/j.tetasy.2003.09.006

Two reliable methods for the synthesis of the enantiomerically pure (S)-3-amino-2-hydroxypropylphosphonic acid (a phosphonate analogue of L-GABOB) from diethyl (S)-2,3-epoxypropylphosphonate are elaborated. The amplification of the enantiomeric purity of

Full text of DOI:10.1016/j.tetasy.2003.09.006

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3359–3363
An efficient synthesis of an enantiomerically pure phosphonate
analogue of -GABOB
L
Andrzej E. Wro´blewski* and Anetta Hałajewska-Wosik
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, 90-151 Ło´dz´, Muszyn´skiego 1, Poland
Received 15 July 2003; accepted 5 September 2003
Abstract—Two reliable methods for the synthesis of the enantiomerically pure (S)-3-amino-2-hydroxypropylphosphonic acid (a
phosphonate analogue of
L-GABOB) from diethyl (S)-2,3-epoxypropylphosphonate are elaborated. The amplification of the
enantiomeric purity of the intermediate diethyl (S)-3-(tert-butoxycarbonylamino)- and (S)-3-(diphenylmethylamino)-2-hydroxy-
propylphosphonates was observed on a silica gel column.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
and including the resolution of the intermediate
dimethyl 3-(N,N-dibenzylamino)-2-hydroxypropylphos-
phonate35 with (S)-O-methylmandelic acid has been
described.36 Herein, we report a four-step approach to
(S)-2 which takes advantage of the hydrolytic kinetic
resolution (HKR) of the racemic diethyl 2,3-
epoxypropylphosphonate in the presence of the Jacob-
sen’s catalyst.35,37,38
(R)-4-Amino-3-hydroxybutyric acid ( -GABOB) 1 is an
L
important aminoacid which acts as an agonist of g-
aminobutyric acid (GABA).1,2 As a neuromodulator it
has been tried in the treatment of several illnesses
including epilepsy.3,4 For these reasons, many methods
for the synthesis of 1 have been reported. They are
based on a chiral pool methodology,5–14 asymmetric
synthesis15–22 and enzymatic or chemoenzymatic
technologies.23–28
2. Results and discussion
Inspection of the 31P NMR spectrum of the crude
product obtained from the racemic 3 and 25% aqueous
ammonia31 led to the conclusion that diethyl 3-amino-
2-hydroxypropylphosphonate was indeed the major
constituent of the reaction mixture, but it was however
contaminated with several organophosphorus com-
pounds, most of which still remain unidentified.39 Due
to the enantiomeric purity of the optically active epox-
ide 3 produced by HKR being at best 94%, we looked
for amines, which would selectively open the oxirane
ring in 3 at C(3) and lead to crystalline aminoalcohols.
A number of phosphonate analogues of GABA have
been synthesised in recent years and have been used for
subtype receptor selectivity studies.29,30 Although a
phosphonate analogue of GABOB was described as
early as 196931 with another method communicated in
1983,32 the optically active 2 (e.e. 92%) has only
recently been obtained chemoenzymatically by Bakers
yeast reduction of diethyl 3-azido-2-oxopropylphospho-
nate followed by catalytic hydrogenation of the azido
group.33,34 However, this methodology is closely related
to that described for 1.26,27 Very recently, an eight-step
sequence to both enantiomers of 2 starting from glycine
Our first strategy to the phosphonate analogue of
L-
GABOB (S)-2 is illustrated in Scheme 1.
When a 1.5:1 mixture of tritylamine and (S)-3 was kept
in toluene solution at 100°C for 7 days, the phospho-
nate (S)-4 was obtained as a single product of the
reaction. The excess of tritylamine was easily removed
on a silica gel column. After crystallisation of the
appropriate fractions, pure phosphonate was isolated.
We noticed that at the same time the e.e. of (S)-4 was
* Corresponding author. Fax: 48-42-678-83-98; e-mail: aewplld@
ich.pharm.am.lodz.pl
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.006

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A. E. Wro´blewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 14 (2003) 3359–3363
The reaction of enantiomerically enriched (S)-3 (e.e.
80%) with one equivalent of benzhydrylamine allowed
for the chromatographic separation of (S)-6 in 77%
yield as a yellowish oil, which did not crystallise. How-
ever, the product was shown to be enantiomerically
pure by 31P NMR analysis using quinine as an enan-
tiodifferentiating compound.40 In another experiment
(S)-3 (e.e. 85%) was used and the enantiomeric compo-
sition of the monophosphonate (S)-6 in the crude
product estimated as 90%. After column chromatogra-
phy on silica gel again, enantiomerically pure (S)-6 was
obtained in 77% yield. Finally, (S)-3 (e.e. 90%) was
transformed into a crude (S)-6 (e.e. 96%), which was
refined on a silica gel to give an enantiomerically pure
product.
Scheme 1. Reagents and conditions: a. TrNH2, 100°C, 7 days;
b. H2–Pd/C, Boc2O; c. 12 M HCl; propylene oxide.
significantly increased. Thus, from (S)-3 (e.e. 74%), the
aminoalcohol (S)-4 (e.e. 96%) was produced. Applica-
tion of (S)-3 (e.e. 85%) led again to (S)-4 (e.e. 96%)
after crystallisation. The same enantiomeric purity of
(S)-4 was found for the crystallised sample obtained
from the epoxide (S)-3 of the highest e.e. (94%). Unfor-
tunately, further crystallisation did not improve the
enantiomeric composition.
The formation of the tertiary amine 7 as a meso/dl
mixture was demonstrated by reacting 2.3 equiv. of
racemic 3 with one equivalent of benzhydrylamine at
100°C for 115 h. The crude product, which still con-
tained some unreacted epoxide
3 (2%) and the
monophosphonate 6 (12%), was chromatographed to
give meso/dl-7 as a colourless oil in 50% yield.
The trityl group was removed by hydrogenolysis in the
presence of Boc2O to afford the N-Boc derivative (S)-5
as an oil, which after column chromatography was
found to be enantiomerically pure. Finally, hydrolysis
of the ester groups in (S)-5 followed by standard treat-
ment with propylene oxide led to (S)-2.
Transformation of the enantiomerically pure (S)-6 into
the N-Boc derivative (S)-5 was accomplished by hydro-
genation over Pd-C in the presence of Boc2O (Scheme
3). We noticed that a crude (S)-5 was contaminated
with (S)-8 (14%), when the reaction was carried out for
24 h, while after 120 h the amount of (S)-8 dropped
down to 5%. The by-product (S)-8 was cleanly sepa-
rated from the more polar (S)-5 on a silica gel column,
and the enantiomerically pure samples of (S)-5 were
obtained in 81 and 90% yield, respectively.
Another method for the synthesis of enantiomerically
pure (S)-2 was developed, when the reaction of the
epoxide (S)-3 with benzhydrylamine was studied
(Scheme 2).
Initially the racemic epoxide 3 was used and we found
that the opening of the oxirane ring in 3 with benz-
hydrylamine led to the formation of diethyl 2-hydroxy-
3-(diphenylmethylamino)propylphosphonate 6 and bis-
N,N - [2 - hydroxy - 3 - (diethoxyphosphoryl)propyl] - N-
(diphenylmethyl)amine 7 in a 92:8 ratio. The bisphos-
phonate 7 was found to be a ca 1:1 meso/dl mixture.
The major product 6 was separated from 7 on a silica
gel column and the monophosphonate 6 was obtained
in 78% yield after crystallisation. It is noteworthy that
crystallisation of the crude product was not effective
in removing meso/dl-7 from 6.
3. Conclusions
The epoxide ring in the phosphonate (S)-3 was regiose-
lectively opened at C(3) with trityl- and benzhydryl-
amines. While the N-tritylphosphonate (S)-4 was too
sterically crowded to react with another molecule of
(S)-3, the N-benzhydrylphosphonate (S)-6 used up
some of the epoxide 3 to produce the bisphosphonate 7
(ca 8%). Although enantiomerically enriched samples of
(S)-3 (e.e. 74–94%) were used, enantiomerically pure
phosphonate (S)-5 (via N-trityl derivative) and (S)-6
Scheme 2. Reagents and conditions: (a) Ph2CHNH2, 100°C, 24 h.
Scheme 3. Reagents and conditions: (a) H2, 10% Pd-C, Boc2O.

A. E. Wro´blewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 14 (2003) 3359–3363
3361
(via N-benzhydryl derivative) were obtained after chro-
matography on silica gel. The phosphonate (S)-5 (N-
Boc) was transformed into the enantiomerically pure
4.2. Diethyl 2-hydroxy-3-(diphenylmethylamino)-
propylphosphonate, 6
phosphonate analogue of
dard conditions.
L
-GABOB (S)-2 under stan-
A mixture of the racemic epoxide 3 (1.00 g, 5.15 mmol)
and benzhydrylamine (0.89 mL, 5.15 mmol) was main-
tained at 100°C for 24 h under argon atmosphere. The
crude product was chromatographed on a silica gel
column with methylene chloride–methanol (50:1, v/v).
The appropriate fractions were collected and crys-
tallised from diethyl ether–hexanes to give the phospho-
4. Experimental
1H NMR spectra were recorded with a Varian Mer-
cury-300 spectrometer; chemical shifts d in ppm with
respect to TMS; coupling constants J in Hz. 13C and
31P NMR spectra were recorded on a Varian Mercury-
300 machine at 75.5 and 121.5 MHz, respectively,
except for the 13C NMR spectrum of (S)-2, which was
taken with a Bruker DPX (250 MHz) spectrometer at
62.9 MHz. IR spectral data were measured on an
Infinity MI-60 FT-IR spectrometer. Melting points
were determined on a Boetius apparatus and are uncor-
rected. Elemental analyses were performed by the
Microanalytical Laboratory of this Faculty on a Perkin
Elmer PE 2400 CHNS analyzer. Polarimetric measure-
ments were conducted on a Perkin Elmer 241 MC
apparatus.
nate
6 (1.52 g, 78%) as white crystals. M.p.
67.5–69.0°C. IR (KBr): w=3294, 3061, 2984, 2924,
2799, 2730, 1603, 1493, 1466, 1449, 1223, 1117, 1059,
1
1028, 964, 742, 701 cm−1. H NMR (CDCl3, 300 MHz):
l=1.31 (t, J=7.0 Hz, 6H), 1.92 (ddd, J1a-P=18.9 Hz,
J
J
1a-1b=15.3 Hz, J1a-2=3.7 Hz, 1H, H-1a), 2.04 (ddd,
1b-P=15.5 Hz, J1a-1b=15.3 Hz, J1b-2=8.9 Hz, 1H, H-
1b), 2.61 (dd, J3a-3b=12.0 Hz, J3a-2=7.4 Hz, 1H, H-3a),
2.76 (dd, J3a-3b=12.0 Hz, J3b-2=3.7 Hz, 1H, H-3b),
4.04–4.18 (m, 5H, OCH2, H-2), 4.85 (s, 1H, HCPh2),
7.18–7.40 (m, 10H, Harom); 13C NMR (75.5 MHz,
CDCl3): l=16.6 (2×d, J=6.1 Hz), 31.6 (d, J=139.0
Hz, C-1), 54.3 (d, J=16.6 Hz, C-3), 62.0 (d, J=5.9 Hz,
CH2O), 65.8 (d, J=4.6 Hz, C-2), 67.3 (s, CHPh2),
127.1, 127.3, 127.3, 128.5, 128.5, 143.7, 143.9; 31P NMR
(121.5 MHz, CDCl3): l=31.28. Anal. calcd for
C20H28NO4P: C, 63.65; H, 7.50; N, 3.71. Found: C,
63.87; H, 7.90; N, 4.05%.
Racemic 3 was prepared according to the literature
procedure in 60% yield (l 31P 26.71 ppm).31,41 Before
estimation of e.e.’s, values and the separation of the 31P
NMR resonances of diastereoisomeric (S)-O-methyl-
mandelic acid derivatives were assigned using racemic 4
and 5. The optimised (S)-6 to quinine ratio was estab-
lished taking 31P NMR spectra for 1:1, 1:2, 1:3, 1:4 and
1:5 (w/w) mixtures of racemic 6 and quinine.
4.2.1. Diethyl (S)-2-hydroxy-3-(diphenylmethylamino)-
propylphosphonate, (S)-6. This compound was obtained
from (S)-3 (617 mg, 3.18 mmol) (e.e. 85%) and benz-
hydrylamine (0.550 mL, 3.18 mmol) as described above.
Chromatographic purification gave (S)-6 (0.924 g, 77%)
as a yellowish oil. [h]2D0=−4.05 (c=2.0 in CHCl3), e.e
100%; Anal. calcd for C20H28NO4Px1/2 H2O: C, 62.17;
H, 7.56; N, 3.60. Found: C, 61.94; H, 7.55; N, 3.32%.
In a similar manner, (S)-6 was obtained from (S)-3 (e.e.
90%) in 74% yield after column chromatography.
[h]2D0=−3.95 (c=2.1 in CHCl3).
4.1. Diethyl (S)-2-hydroxy-3-(triphenylmethylamino)-
propylphosphonate, (S)-4
A solution of the epoxide (S)-3 (750 mg, 3.86 mmol)
and tritylamine (1.50 g, 5.79 mmol) in toluene (5 mL)
was maintained under argon at 100°C for 7 days. After
evaporation of solvents, the residue was chro-
matographed on a silica gel column with methylene
chloride–methanol mixtures (100:1, v/v). Appropriate
fractions were collected and crystallised from diethyl
ether–petroleum ether to give (S)-4 (1.33 g, 76%) as a
white solid. M.p. 80–81°C. [h]2D0=−5.6 (c=3.3 in
CHCl3), e.e. 96%; IR (KBr): w=3437, 3080, 2980, 2925,
4.3. Bis-N,N-[2-hydroxy-3-(diethoxyphosphoryl)propyl]-
N-(diphenylmethyl)amine, 7
A mixture of the racemic epoxide 3 (1.15 g, 5.87 mmol)
and benzhydrylamine (0.444 mL, 2.58 mmol) was main-
tained at 100°C for 115 h. The crude product was
chromatographed on a silica gel column with methylene
chloride–methanol (100:1, v/v) to give 7 (736 mg, 50%)
as a yellowish oil. IR (film): w=3372, 3060, 2982, 2931,
2908, 1493, 1448, 1392, 1223, 1164, 1029, 963, 833, 808,
765, 736, 704 cm−1; 1H NMR (300 MHz, CDCl3):
l=1.27 and 1.28 (2t, J=7.0 Hz, 12H, CH3 in meso-7),
1.30 (t, J=7.0 Hz, 12H, CH3 in dl-7), 1.65–1.91 (m, 4H,
H2CP), 2.61–2.73 (m, 4H, CH2N in dl-7), 2.73 (dd,
J=14.0 Hz, J=8.7 Hz, 2H, HCHN in meso-7), 2.93
(dd, J=14.0 Hz, J=3.2 Hz, 2H, HCHN in meso-7),
3.90–4.10 (m, 10H, CH2OP, HCOH), 4.3 (brs, 2H,
OH), 5.05 (s, HCPh2 in dl-7), 5.17 (s, HCPh2 in meso-
7), 7.2–7.4 (m, 10H, Harom); 13C NMR (75.5 MHz,
CDCl3): l=16.7 (d, J=6.0 Hz), 31.5 and 31.6 (2d,
J=139.7 Hz, CP), 58.5 (d, J=17.6 Hz, CN), 60.4 (d,
1
2851, 1489, 1448, 1225, 1027, 754, 710 cm−1; H NMR
(CDCl3, 300 MHz): l=1.30 and 1.32 (2 t, J=6.9 Hz,
6H), 1.94 (ddd, J1a-P=19.0 Hz, J1a-1b=15.3 Hz, J1a-2
3.4 Hz, 1H, H-1a), 2.05 (ddd, J1b-1a=15.3 Hz, J1b-P
=
=
15.1 Hz, J1b-2=9.1 Hz, 1H, H-1b), 2.08–2.15 (brs, 1H,
NH), 2.24 and 2.29 (AB part of ABX system, J3a-3b
=
11.5 Hz, J2-3a=7.1 Hz, J2-3b=3.9 Hz, 2H, H-3a, 3b),
3.63 (d, J=2.4 Hz, 1H, OH), 4.03–4.20 (m, 5H,
CH2OP, H-2), 7.15–7.47 (m, 15H); 13C NMR (CDCl3,
75.5 MHz): l=16.7 (2d, J=6.0 Hz, CH3), 31.9 (d,
J=139.0 Hz, C-1), 50.2 (d, J=17.8 Hz, C-3), 62.0 and
62.1 (2d, J=6.3 Hz, CH2O), 66.8 (d, J=4.9 Hz, C-2),
70.6, 126.4, 127.9, 128.7, 145.9; 31P NMR (CDCl3,
121.5 MHz): l=30.78. Anal. calcd for C26H32NO4P: C,
68.86; H, 7.11; N, 3.09. Found: C, 68.68; H, 7.34; N,
3.14%.

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J=18.0 Hz, CN), 61.9 and 62.1 (2d, J=6.0 Hz,
CH2OP), 64.6 and 66.1 (2s, HCO), 71.3 (s, NCHPh2),
127.1, 127.2, 127.4, 128.2, 128.4, 129.1, 129.3, 129.6,
140.2, 141.0, 141.6; 31P NMR (121.5 MHz, CDCl3):
l=30.19 (dl-7), 30.28 (meso-7). Anal. calcd for
C27H43NO8P2: C, 56.74; H, 7.58; N, 2.45. Found: C,
56.53; H, 7.91; N, 2.80%.
(d, J=139.5 Hz, C-1), 52.5 (brd, J$18.0 Hz, C-3), 61.8
and 61.9 (2d, J=6.0 Hz), 65.2 (brs), 67.0 (brs, C-2),
81.2, 127.4, 127.6, 128.5, 129.0, 140.0, 140.0, 156.8
(brs); 31P NMR (CDCl3, 121.5 MHz): l=29.85. Anal.
calcd for C25H36NO6Px1/4 H2O: C, 62.29; H, 7.63; N,
2.83. Found: C, 62.22; H, 7.84; N, 3.04.
Further elution afforded (S)-5 as a colourless oil (156
mg, 81%), [h]2D0=−2.1 (c=3.1 in CHCl3).
4.4. Diethyl (S)-3-[(tert-butoxycarbonyl)amino]-2-
hydroxypropylphosphonate, (S)-5
4.6. General procedures for the estimation of e.e.’s
4.4.1. From the N-tritylphosphonate (S)-4. A solution of
(S)-4 (391 mg, 0.862 mmol) in ethanol (3 mL) contain-
ing Boc2O (207 mg, 0.948 mmol) was hydrogenated
over 10% Pd–C (9 mg) under atmospheric pressure for
24 h. The catalyst was removed with filtration through
Celite and the solution concentrated and chro-
matographed on a silica gel column with a methylene
chloride–methanol mixture (50:1, v/v) to give (S)-5 (219
mg, 82%) as a colourless hygroscopic oil. [h]2D0=−2.6
(c=2.8 in CHCl3); IR (film): w=3350, 2977, 2920, 2851,
1716, 1686, 1522, 1456, 1367, 1252, 1161, 1057, 1031
4.6.1. N-Tritylphosphonates (S)-4. (S)-O-Methylman-
delic acid (11 mg, 0.066 mmol), DCC (14 mg, 0.066
mmol) and one crystal of DMAP were added to a
solution of (S)-4 (20 mg, 0.044 mmol) in CH2Cl2 (1.5
mL). The reaction mixture was stirred at room temper-
ature for 24 h under argon atmosphere. 1,3-Dicyclo-
hexylurea was filtered off and the solution was
concentrated. The residue was dissolved in CDCl3 (0.7
mL) and the solution analysed by 31P NMR spec-
troscopy. (S)-O-Methylmandelic acid esters of (S)-4:
31P NMR (CDCl3, 121.5 MHz): l=26.82 (S,S-
diastereoisomer), 27.01 (R,S-diastereoisomer).
1
cm−1; H NMR (CDCl3, 300 MHz): l=1.34 and 1.35
(2t, J=7.0 Hz, 6H), 1.45 (s, 9H), 1.85–2.02 (m, 2H,
H2CP), 3.15 (dt, J3a-3b=12.1 Hz, J3a-2=6.0 Hz, 1H,
H-3a), 3.38 (very broad d, J3a-3b=12.1 Hz, 1H, H-3b),
3.99 (s, 1H, OH), 4.03–4.20 (m, 5H, H2CO, H-2), 5.05
(brt, J$5.0 Hz, NH); 13C NMR (CDCl3, 75.5 MHz):
l=16.6 (2d, J=6.3 Hz), 28.6, 31.0 (d, J=139.4 Hz,
C-1), 46.9 (d, J=17.7 Hz, C-3), 62.1 and 62.2 (2d,
J=6.3 Hz), 66.3 (d, J=3.7 Hz, C-2), 79.6, 156.6; 31P
NMR (CDCl3, 121.5 MHz): l=30.23. Anal. calcd for
C12H26NO6Px1/4 H2O: C, 45.64; H, 8.46; N, 4.43.
Found: C, 45.71; H, 8.63; N, 4.36%.
4.6.2. N-Boc-phosphonates (S)-5. The procedure
described above was followed using (S)-O-methylman-
delic acid (8.8 mg, 0.053 mmol), DCC (11 mg, 0.053
mmol), one crystal of DMAP and (S)-5 (11 mg, 0.035
mmol). (S)-O-Methylmandelic acid esters of (S)-5: 31P
NMR (CDCl3, 121.5 MHz): l=26.62 (S,S-
diastereoisomer), 26.79 (R,S-diastereoisomer).
4.6.3. N-Benzhydrylphosphonates (S)-6. A solution of
(S)-6 (15 mg, 0.040 mmol) in CDCl3 (0.7 mL) contain-
ing quinine (75 mg, 0.23 mmol) was analysed by 31P
NMR spectroscopy. 31P NMR (CDCl3, 121.5 MHz):
l=30.55 [(S)-6], 30.35 [(R)-6]. For analyses of crude
products containing (S)-6, the amounts of the com-
pounds were doubled.
4.4.2. From the N-benzhydrylphosphonate (S)-6. A solu-
tion of (S)-6 (268 mg, 0.710 mmol) and Boc2O (168 mg,
0.770 mmol) in absolute ethanol (3 mL) was kept under
hydrogen (balloon) in the presence of 10% Pd–C (15
mg) for 120 h. The suspension was filtered through
Celite and the solution concentrated. The crude
product was chromatographed as described above to
give (S)-5 (183 mg, 90%) as a colourless oil identical in
all respects with the material obtained from (S)-4.
4.7. (S)-3-Amino-2-hydroxypropylphosphonic acid, (S)-
2
A mixture of the phosphonate (S)-5 (143 mg, 0.460
mmol) and aqueous HCl (12 M, 1 mL) was refluxed for
3 days. Volatiles were evaporated, and the residue
coevaporated with anhydrous ethanol (5x3 mL). A
solution of the crude product in ethanol (1 mL) was
treated dropwise with propylene oxide to pH 7. The
precipitate was filtered off and chromatographed on a
silanized silica gel column using water to give (S)-2 (57
mg, 78%) as a white very hygroscopic powder, which
decomposed before melting. [h]2D0=−41.4 (c=0.9 in
H2O); IR (KBr): w=3423, 2923, 2852, 1638, 1535, 1155,
4.5. Diethyl (S)-3-[tert-butoxycarbonyl(diphenyl-
methyl)amino]-2-hydroxypropylphosphonate, (S)-8
A solution of (S)-6 (234 mg, 0.620 mmol) and Boc2O
(149 mg, 0.680 mmol) in absolute ethanol (3 mL) was
kept under hydrogen in the presence of 10% Pd-C (15
mg) for 24 h. The crude product obtained as described
in 4.4.2. was chromatographed on a silica gel column
with methylene chloride–methanol (50:1, v/v) to give
(S)-8 (35 mg, 11%) as a colourless oil. [h]2D0=+6.6
(c=1.9 in CHCl3); IR (film): w=3363, 2980, 2931, 1690,
1453, 1394, 1251, 1030, 756, 702 cm−1; 1H NMR
(CDCl3, 300 MHz): l=1.26 and 1.27 (2d, J=7.0 Hz,
6H), 1.35 (brs, 9H), 1.56–1.72 (m, 2H, H-1a,b), 2.0–2.6
(brs, 1H, OH), 3.53 (dd, J3a-3b=14.3 Hz, J3a-2=3.9 Hz,
1H, H-3a), 3.50–3.70 (brm, 2H, H-2,3b), 3.94–4.07 (m,
4H), 6.34 (brs, 1H), 7.16–7.38 (m, 10H); 13C NMR
(CDCl3, 75.5 MHz): l=16.6 (d, J=6.0 Hz), 28.4, 32.1
1
1057, 994 cm−1; H NMR (D2O, 300 MHz): l=1.89
(ddd, J1a-1b=15.2 Hz, J1a-P=17.6 Hz, J1a-2=7.1 Hz,
1H, H-1a), 1.98 (ddd, J1a-1b=15.2 Hz, J1b-P=18.5 Hz,
J
J
J
J
1b-2=6.5 Hz, 1H, H-1b), 2.99 (dd, J3a-3b=13.2 Hz,
3a-2=9.6 Hz, 1H, H-3a), 3.31 (dd, J3a-3b=13.2 Hz,
3b-2=3.0 Hz, 1H, H-3b), 4.17 (ddddd, J2-3a=9.6 Hz,
2-P=8.9 Hz, J2-1a=7.1 Hz, J2-1b=6.5 Hz, J2-3b=3.0
Hz, 1H, H-2); 13C NMR (D2O/DSS, 62.9 MHz): l=

A. E. Wro´blewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 14 (2003) 3359–3363
3363
36.4 (d, J=130.6 Hz, C-1), 47.7 (d, J=10.5 Hz, C-3),
66.8 (s, C-2); 31P NMR (D2O, 121.5 MHz): l=20.43.
HRMS (FAB+) C3H10NO4P (m/z): calcd 156.0438.
Found 156.0423.
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